Principles of Clinical Pharmacology
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Transcript of Principles of Clinical Pharmacology
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Principles of Clinical Pharmacology
Noncompartmental versus Compartmental Approaches to Pharmacokinetic Data Analysis
David Foster, Professor EmeritusDepartment of Bioengineering
University of Washington
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Questions asked• What does the body do to the drug?
Pharmacokinetics• What does the drug do to the body?
Pharmacodynamics• What is the effect of the drug on the body?
Disease progression and management• What is the variability in the population?
Population pharmacokinetics
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What is needed?
• A means by which to communicate the answers to the previous questions among individuals with diverse backgrounds
• The answer: pharmacokinetic parameters
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Pharmacokinetic parameters
• Definition of pharmacokinetic parameters• Formulas for the pharmacokinetic
parameters• Methods to estimate the parameters from
the formulas using data
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Pharmacokinetic parameters
• Descriptive or observational• Quantitative (requiring a formula and a
means to estimate using the formula)
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Quantitative parameters
• Formula reflective the definition• Data• Estimation methods
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Models for estimation
• Noncompartmental• Compartmental
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Goals of this lecture
• Description of the quantitative parameters• Underlying assumptions of
noncompartmental and compartmental models
• Parameter estimation methods• What to expect from the results
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Goals of this lecture
• Not to conclude that one method is better than another
• What are the assumptions, and how can these affect the conclusions
• Make an intelligent choice of methods depending upon what information is required from the data
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A drug in the body:constantly undergoing change
• Absorption• Transport in the circulation• Transport across membranes• Biochemical transformation• Elimination
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A drug in the body:constantly undergoing change
How much?What’s happening?
How much?How much?
How much?
How much?
What’s happening?
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Kinetics
The temporal and spatial distribution of a substance in a system.
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Pharmacokinetics
The temporal and spatial distribution of a drug (or drugs) in a system.
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• Spatial: Where in the system• Temporal: When in the system• If are spatial coordinates and
is the measurement of a substance at a specific , then the rate of change of the measurements depends upon and t:
),,( zyx ),( tscc
s
s
ttsc
ztsc
ytsc
xtsc
),(,),(,),(,),(
Definition of kinetics: consequences
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A drug in the body:constantly undergoing change
How much?What’s happening?
How much?How much?
How much?
How much?
What’s happening?
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A drug in the body:constantly undergoing change
How much?What’s happening?
How much?How much?
How much?
How much?
zyxt
,,,
zyxt
,,,
zyxt
,,,
zyxt
,,,
What’s happening?
zyxt
,,,
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Using partial derivatives
• Requires a knowledge of physical chemistry, irreversible thermodynamics and circulatory dynamics.
• Difficult to solve.• Difficult to design an experiment to
estimate parameter values.• While desirable, normally not practical.
• Question: What can one do?
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Resolving the problem
• Reducing the system to a finite number of components
• Lumping processes together based upon time, location or a combination of the two
• Space is not taken directly into account
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Lumped parameter models
• Models which make the system discrete through a lumping process thus eliminating the need to deal with partial differential equations.
• Classes of such models:– Noncompartmental models (algebraic
equations)– Compartmental models (linear or nonlinear
differential equations)
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The system
• Accessible pools: These are pools that are available to the experimentalist for test input and/or measurement.
• Nonaccessible pools: These are pools comprising the rest of the system which are not available for test input and/or measurement.
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An accessible pool
SYSTEM
AP
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Characteristics of the accessible pool
• Kinetically homogeneous• Instantaneous and well-mixed
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Kinetic homogeneity
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Instantaneous and well-mixed
S1
S2
S1
S2
BA
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Instantaneous and well-mixed
LA
LV
RA
RV
LUNG
SPLEEN
GI LIVER
KIDNEY
MUSCLE
OTHER
BRAIN
S1 S2
S3
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The single accessible pool
SYSTEM
AP
E.g. Direct input into plasma with plasma samples.
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The two accessible pools
SYSTEM
AP AP
E.g. Oral dosing or plasma and urine samples.
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The pharmacokinetic parameters
The pharmacokinetic parameters estimated using kinetic data characterize both the kinetics in the accessible pool, and the kinetics in the whole system.
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Accessible pool parameters
• Volume of distribution• Clearance rate• Elimination rate constant• Mean residence time
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System parameters
• Equivalent volume of distribution• System mean residence time• Bioavailability• Absorption rate constant
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Models to estimate the pharmacokinetic parameters
The difference between noncompartmental and compartmental models is how the nonaccessible portion of the system is described.
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The noncompartmental model
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Single accessible pool model
SYSTEM
AP AP
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Two accessible pool model
SYSTEM
AP AP 1 2
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Recirculation-exchange arrow
APRecirculation/Exchange
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Recirculation-exchange arrow
APRecirculation/Exchange
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Single accessible pool model
• Parameters (bolus and infusion)• Estimating the parameters from data
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Single accessible pool model parameters
)0(CdVa
)0(CuVa
AUCdCLa
CuCLa
AUCAUMCMRTs
C
dttCCMRTs
0
)]([
Bolus Infusion
d – dose; u – infusion rate; C(t) – concentration; AUC – area under curve (1st moment); AUMC – mean area under curve (2nd moment); – steady state concentration.C
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What is needed?
• Estimates for C(0), and/or .• Estimates for AUC and AUMC.
All require extrapolations beyond the time frame of the experiment. Thus this method is not model independent as often claimed.
)0(C C
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The integrals
n
n
t
t
t
tdttCdttCdttCdttCAUC )()()()(
1
1
00
n
n
t
t
t
tdttCtdttCtdttCtdttCtAUMC )()()()(
1
1
00
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Estimating AUC and AUMC using sums of exponentials
tn
t neAeAtC 11)(
tn
t neAeAAtC 110)(
010 nAAA
Bolus
Infusion
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Bolus Injection
0
1
1)(n
nAAdttCAUC
0 22
1
1)(n
nAAdttCtAUMC
And in addition:
nAAC 1)0(
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Infusion
n
nAAdttCC
1
10
)]([
And in addition:
nnAAC 11)0(
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Estimating AUC and AUMC using other methods
• Trapezoidal • Log-trapezoidal• Combinations• Other• Extrapolating
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The Integrals
n
n
t
t
t
tdttCdttCdttCdttCAUC )()()()(
1
1
00
n
n
t
t
t
tdttCtdttCtdttCtdttCtAUMC )()()()(
1
1
00
The other methods provide formulas for the integrals betweent1 and tn leaving it up to the researcher to extrapolate to time zero and time infinity.
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Trapezoidal rule
))(()((21
111 iiiobsiobsii tttytyAUC
))(()((21
1111 iiiobsiiobsiii tttyttytAUMC
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Log-trapezoidal rule
))(()((
)()(ln
111
1
1
iiiobsiobs
iobs
iobs
ii tttyty
tyty
AUC
))(()((
)()(ln
1111
1
1
iiiobsiiobsi
iobs
iobs
ii tttyttyt
tyty
AUMC
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Extrapolating from tn to infinity
• Terminal decay is a monoexponential often called z.
• Half-life of terminal decay calculated:tz/1/2 = ln(2)/ z
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Extrapolating from tn to infinity
nt z
nobsdatextrap
tydttCAUC
)()(
nt z
nobs
z
nobsndatextrap
tytytdttCtAUMC 2
)()()(
From last datum:
From last calculated value:
n
nz
tz
tz
calcextrapeAdttCAUC
)(
n
nznz
tz
tz
z
tzn
calcextrapeAeAtdttCtAUMC 2)(
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Estimating the Integrals
n
n
t
t
t
tdttCdttCdttCdttCAUC )()()()(
1
1
00
n
n
t
t
t
tdttCtdttCtdttCtdttCtAUMC )()()()(
1
1
00
To estimate the integrals, one sums up the individualcomponents.
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Advantages of using sums of exponentials
• Extrapolation done as part of the data fitting• Statistical information of all parameters
calculated• Natural connection with the solution of
linear, constant coefficient compartmental models
• Software easily available
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The Compartmental Model
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Single Accessible Pool
SYSTEM
AP AP
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Single Accessible Pool
APAP
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PLASMA
INPUT
A
C B
D
++
-
PLASMACONCENTRATION
SAMPLES
TIME
Key Concept: Predicting inaccessible features of the system based upon measurements in the accessible pool, while estimating specific parameters of interest.
Inaccessible Pools Accessible Pool
A model of the system
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A model of the system
Accessible Room
Inaccessible Rooms
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Compartmental model
• Compartment– instantaneously well-mixed– kinetically homogeneous
• Compartmental model– finite number of compartments– specifically connected– specific input and output
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Kinetics and the compartmental model
),,,(,,, tzyxXtzyx
dtdXtX
dtd )(
Time and Space
Time
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Notation
Fji
Fij
F0i
Fi0
Qi
Fij are transport in units mass/time.
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The Fij
• Describe movement among, into or out of a compartment
• A composite of metabolic activity– transport– biochemical transformation– both
• Similar time frame
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The Fij
)(),,(),,( tQtpQktpQF ijiji
(ref: see Jacquez and Simon)
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The kij
The kij are called fractional transfer functions.
If a ijij ktpQk ),,( is constant, the kij is called
a fractional transfer or rate constant.
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Compartmental models and systems of ordinary differential equations
• Well mixed: permits writing Qi(t) for the ith compartment.
• Kinetic homogeneity: permits connecting compartments via the kij.
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The ith compartment
010
)(),,()(),,( i
n
ijj
jiji
n
ijj
jii FtQtpQktQtpQk
dtdQ
Rate ofchange ofQi
Fractionalloss ofQi
Fractionalinput fromQj
Input from“outside”
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Linear, constant coefficient compartmental models
• All transfer rates kij are constant.
• Assumes “steady state” conditions.
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The ith compartment
010
)()( i
n
ijj
jiji
n
ijj
jii FtQktQk
dtdQ
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The compartmental matrix
n
ijj
jiii kk0
nnnn
n
n
kkk
kkkkkk
K
21
22221
11211
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Compartmental model
• A postulation of how one believes a system functions.
• The need to perform the same experiment on the model as one did in the laboratory.
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Example using SAAM II
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Example using SAAM II
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Example using SAAM II
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Experiments
• Need to recreate the laboratory experiment on the model.
• Need to specify input and measurements• Key: UNITS
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Conceptualization(Model)
Reality (Data)
Data Analysisand Simulation
program optimize begin model … end
Model of the System?
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PLASMA
INPUT
A
C B
D
++
-
PLASMACONCENTRATION
SAMPLES
TIME
Key Concept: Predicting inaccessible features of the system based upon measurements in the accessible pool, while estimating specific parameters of interest.
Inaccessible Pools Accessible Pool
A Model of the System
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DATA
MODEL OUTPUT
12
3
INPUT PHYSIOLOGICALSYSTEM
PARAMETERESTIMATIONALGORITHM
MATHEMATICALMODEL
1 2
Parameter Estimation
MODEL FIT
PARAMETERS
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Parameter estimates
• Model parameters: kij and volumes• Pharmacokinetic parameters:
volumes, clearance, residence times, etc.
• Reparameterization - changing the paramters from kij to the PK parameters.
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Recovering the PK parameters from the compartmental model
• Parameters based upon the model primary parameters
• Parameters based upon the compartmental matrix
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Parameters based upon the model primary parameters
• Functions of model primary parameters
• Clearance = volume * k(0,1)
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Parameters based upon the compartmental matrix
nnnn
n
n
kkk
kkkkkk
K
21
22221
11211
nnnn
n
n
KΘ
21
22221
11211
1
Theta, the negative of the inverse of the compartmental matrix, is called the mean residence time matrix.
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Parameters based upon the compartmental matrix
ij
jiii
ij ,
The average time the drug entering compartment jfor the first time spends in compartment i beforeleaving the system.
The probability that a drug particle incompartment j will eventually pass throughcompartment i before leaving the system.
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Compartmental models:advantages
• Can handle non-linearities• Provide hypotheses about system structure• Can aid in experimental design• Can be used to estimate dosing regimens for
Phase 1 trials
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Noncompartmental versus Compartmental Approaches to PK
Analysis: A Example
• Bolus injection of 100 mg of a drug into plasma. Serial plasma samples taken for 60 hours.
• Analysis using:– WinNonlin (“trapezoidal” integration)– Sums of exponentials– Linear compartmental model
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WinNonlin Sum of Exponentials Compartmental Model
Volume 10.2 (9%) 10.2 (3%)Clearance 1.02 1.02 (2%) 1.02 (1%)MRT 19.5 20.1 (2%) 20.1 (1%) z 0.0504 .0458 (3%) .0458 (1%)AUC 97.8 97.9 (2%) 97.9 (1%)AUMC 1908 1964 (3%) 1964 (1%)
Results
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Take Home Message
• To estimate the traditional pharmacokinetic parameters, either model is probably okay.
• Noncompartmental models cannot help in prediction
• Best strategy is probably a blend of compartmental to understand “system” and noncompartmental for FDA filings.
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Some References• JJ DiStefano III. Noncompartmental vs compartmental
analysis: some bases for choice. Am J. Physiol. 1982;243:R1-R6
• DG Covell et. al. Mean Residence Time. Math. Biosci. 1984;72:213-2444
• Jacquez, JA and SP Simon. Qualitative theory of compartmental analysis. SIAM Review 1993;35:43-79
• Jacquez, JA. Compartmental Analysis in Biology and Medicine. BioMedware 1996. Ann Arbor, MI.
• Cobelli, C, D Foster and G Toffolo. Tracer Kinetics in Biomedical Research. Kluwer Academic/Plenum Publishers. 2000, New York.
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SAAM II
• A general purpose kinetic analysis software tool
• Developed under the aegis of a Resource Facility grant from NIH/NCRR
• Available from the SAAM Institute:http://www.saam.com
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Moments
• Moments play a key role in estimating pharmacokinetic parameters via noncompart-mental models.
• Modern use: Yamaoka, K et al. Statistical moments in pharmacokinetics. J. Pharma. Biopharm. 1978;6:547
• Initial use: Developed in late 1930’s
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Moments
AUCdttCS
00 )(
AUMCdttCtS
01 )(